Why viral stowaways are a baby's best friend

Harmless viruses apparently stowed away for millions of years in the DNA of mammals have proved to be more than idle passengers.

New research in live sheep has demonstrated for the first time that they help embryos change shape, implant themselves in the womb and grow a placenta. The same almost certainly happens in other mammals, including humans, they say.

The findings provide new insights into how so-called endogenous retroviruses (ERVs) and mammals evolved together to the mutual advantage of both. ERVs typically account for 8% to 10% of the DNA in most mammals, including humans.

Far from being relics of infection dumped in the genetic equivalent of an attic, these viruses are turning out to play an active role in the way mammals develop and survive. Besides the role in pregnancy identified by the new research, they are already reckoned to help protect against harmful viruses, a role that could open up new avenues of medical treatment.

Pregnancy loss

Tom Spencer and his colleagues at Texas A&M University in College Station, US, studied the role of ERVs in pregnancy through lab experiments and on live sheep. They already suspected from the lab work on sheep embryos that endogenous Jaagsiekte sheep retroviruses (enJSRVs) help embryos develop.

In the new work, they proved their suspicions correct by injecting the womb linings of sheep with a drug which blocks activity of the virus. The drug was designed to block the specific "envelope" gene of the virus suspected of aiding pregnancy.

Pregnant sheep given the virus-blockers suffered miscarriages. "When production of the envelope protein was blocked in the early placenta, the growth of the placenta was reduced and its development inhibited," says Spencer. "The end result was that the sheep suffered recurrent early pregnancy loss."

"The main message is that endogenous retroviruses are important for reproduction and may have been a major factor shaping evolution of the placenta," says Spencer, who co-led the research with Massimo Palmarini from the University of Glasgow Veterinary School in the UK.

Good virus to catch

"We currently think that enJSRVs arose from ancient infections of small ruminants during their evolution," explains Spencer. Previously, these same ruminants relied on a native gene that had evolved to orchestrate the early stages of pregnancy.

But when the virus embedded itself following infection, it produced a protein which did the job even better, and became part of the ruminant's own, heritable DNA.

Ruminants with the virus gene bred more successfully as a result, so the gene became dominant in the early ruminants and in the sheep which evolved from them. "Now, we know that enJSRVs are found in the DNA of every sheep on the planet," Spencer says.

Moreover, it is likely that there is a human counterpart, called HERV-W, which has been shown in lab studies to do a similar job. But the work in sheep is the first demonstration of the virus's job in live animals.

As well as their role in pregnancy, ERVs are already known to protect against other viruses. In sheep, for example, enJSRVs block the life cycle of related but infectious JSRVs which cause lung cancers and pneumonia in sheep - and which killed Dolly the cloned sheep.

"Adopting" HIV

By finding out more about how enJSRVs function in development of the sheep placenta, Spencer and Palmarini hope to cast more light on how defects in the process might trigger infertility in women. "Our results should have implications for both animal production in agriculture, as well as human health," says Spencer.

Likewise, the potential for ERVs to protect against viruses could yield new ways to treat viral infections, which is why the work was co-funded by the US National Institutes of Health and the UK's Wellcome Trust.

Spencer says that none of the retroviruses "adopted" by the human genome has any surviving infectious counterpart, suggesting that our adopted viruses have "won" the battle for us and wiped out viruses that were previously infectious.

The tantalising implication, he says, is that in years to come we will be protected from today's killer viruses, like HIV and the hepatitis viruses, by endogenous versions which have taken up residence in our own DNA.

Journal reference: Proceedings of the National Academy of Sciences (DOI: 10.1073/pnas.0603836103)

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